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Does In Vitro Potency Predict Clinically Efficacious Concentrations?

Artikel i vetenskaplig tidskrift
Författare R. Jansson-Lofmark
Stephan Hjorth
J. Gabrielsson
Publicerad i Clinical Pharmacology and Therapeutics
ISSN 0009-9236
Publiceringsår 2020
Publicerad vid Institutionen för medicin, avdelningen för molekylär och klinisk medicin
Språk en
Länkar dx.doi.org/10.1002/cpt.1846
Ämnesord plasma-protein binding, compound promiscuity, drug discovery, vivo, pharmacokinetics, inhibitor, target, pharmacodynamics, pharmacology, receptor, Pharmacology & Pharmacy
Ämneskategorier Farmakologi

Sammanfattning

The in vitro affinity of a compound for its target is an important feature in drug discovery, but what remains is how predictive in vitro properties are of in vivo therapeutic drug exposure. We assessed the relationship between in vitro potency and clinically efficacious concentrations for marketed small molecule drugs (n = 164) and how they may differ depending on therapeutic indication, mode of action, receptor type, target localization, and function. Approximately 70% of compounds had a therapeutic unbound plasma exposure lower than in vitro potency; the median ratio of exposure in relation to in vitro potency was 0.32, and 80% had ratios within the range of 0.007 to 8.7. We identified differences in the in vivo-to-in vitro potency ratio between indications, mode of action, target type, and matrix localization, and whether or not the drugs had active metabolites. The in vitro-assay variability contributions appeared to be the smallest; within the same drug target and mode of action the within-variability was slightly broader; but both were substantially less compared with the overall distribution of ratios. These data suggest that in vitro potency conditions, estimated in vivo potency, required level of receptor occupancy, and target turnover are key components for further understanding the link between clinical drug exposure and in vitro potency.

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